Pain is an unpleasant sensation varying in severity in a local part of the body or several parts of the body resulting from injury, disease, or emotional disorder. Pain can be classified according to its duration. Acute pain, which lasts less than one month, usually has a readily identifiable cause and signals tissue damage. In addition, acute pain syndromes can be episodic, for example recurrent discomfort from arthritis. Chronic pain can be defined as pain that persists more than one month beyond the usual course of an acute illness or injury, or pain that recurs at intervals over months or years, or pain that is associated with a chronic pathologic process. In contrast to acute pain, chronic pain loses its adaptive biologic function. Depression is common, and abnormal illness behavior often compounds the patient's impairment.
Millions of people suffer from chronic or intractable pain. Persistent pain varies in etiology and presentation. In some cases, symptoms and signs may be evident within a few weeks to a few months after the occurrence of an injury or the onset of disease, e.g., cancer or AIDS. Like many illnesses that at one time were not well understood, pain and its many manifestations may be poorly treated and seriously underestimated. Inappropriately treated pain seriously compromises the patient's quality of life, causing emotional suffering and increasing the risk of lost livelihood and disrupted social integration. Severe chronic pain affects both the pediatric and adult population, and often leads to mood disorders, including depression and, in rare cases, suicide.
In the last several years, health policy-makers, health professionals, regulators, and the public have become increasingly interested in the provision of better pain therapies. This interest is evidenced, in part, by the U.S. Department of Health and Human Services' dissemination of Clinical Practice Guidelines for the management of acute pain and cancer pain. There is currently no nationally accepted consensus for the treatment of chronic pain not due to cancer, yet the economic and social costs of chronic pain are substantial, with estimates ranging in the tens of billions of dollars annually.
Different classes of drugs are currently available for pain management, nonsteriodal anti-inflammatories, opioids, and adjuvant analgesics. The nonsteriodal anti-inflammatories class includes drugs such as aspirin, ibuprofen, diclofenac, acetaminophen, celecoxib, and rofecoxib. The opioid class includes morphine, oxycodone, fentanyl, and pentazocine. Adjuvant analgesics include various antidepressants, anticonvulsants, neuroleptics, corticosteroids and ion channel-blocking agents, such as carbamazepine (Na+) and ziconotide (Ca+2).
Sodium channel-blocking agents have been reported to be effective in the treatment of pain and various disease states. Anger et al. J. Med. Chem. 44(2), 115-137 (2001). They are particularly useful as local anesthetics, and in the treatment of cardiac arrhythmia. Sodium channel blockers have also been used as anticonvulsants and as neuroprotective agents for treating stroke and other brain injuries. Recently, sodium channel blockers have also proven useful in the treatment of tinnitus, commonly known as ringing of the ear (Murai et al. American Journal of Otology, 13(5), 454-464 (1992)). It has also been reported for many years that sodium channel-blocking agents may be useful in the treatment of pain, including neuropathic pain; see, for example, Tanelian et al., Pain Forum., 4(2), 75-80, (1995). There is evidence that sodium channel-blocking agents selectively suppress ectopic neural firing in injured nerves, and it is by this mechanism that they are believed to be useful for relieving pain. Studies carried out on well known sodium channel-blocking agents, for example carbamazepine, phenytpin, lidocaine, mexiletine, and the like, have shown them to be useful against various types of neuropathic pain conditions.
However, pain relief has often been obtained concomitantly with numerous adverse events and/or limitations in efficacy which have restricted tolerability of these drugs. This difficulty may be due to the disparate activities outlined above, which in turn may arise, in part, because many of the above compounds block more than one type of ion channel. For example, lidocaine and bupivacaine bind potassium channels, and it is believed that this activity is responsible for their cardiotoxic effects. A selective sodium channel blocking agent may provide increased specificity of action, reducing unwanted side effects, and permitting more freedom to vary dosage for treating the primary disorder without inducing seizures or cardiac malfunction.
Calcium channel-blocking agents have also been shown to reduce pain behaviors, mechanical hyperalgesia and allodynia. Selective voltage sensitive calcium channel blockes have been shown to be effective analgesics. Recently, ziconotide, has been reported to be effective in treating severe neuropathic pain [Hu et al. Bioorganic & Medicinal Chemistry Letters 9: 2151-2156 (1999)]. Also, co-administration of ziconotide and morphine, an opioid agonist, produced an additive or synergistic analgesic effect, see Wang et al. Pain 84: 271-281 (2000).
Opioids are the major class of analgesics used in the management of moderate to severe pain because of their effectiveness, ease of titration, and favorable risk-to-benefit ratio. Opioids produce analgesia by binding to specific receptors both within and outside the CNS. Opioid analgesics are classified as full agonists, partial agonists, or mixed agonist-antagonists, depending on the receptors to which they bind and their intrinsic activities at each receptor.
Three subclasses of opioid receptor have been identified in humans, namely the δ-, κ-, and μ-opioid receptors. Analgesia is thought to involve activation of μ and/or κ receptors. Notwithstanding their low selectivity for μ over κ receptors, it is likely that morphine and morphine-like opioid agonists produce analgesia primarily through interaction with μ receptors; selective agonists of κ receptors in humans produce analgesia, because rather than the euphoria associated with morphine and congeners, these compounds often produce dysphoria and psychotomimetic effects. The consequences of activating δ receptors in humans remain unclear.
Although opioids can be very effective in pain management, they do cause several side effects, such as respiratory depression, constipation, physical dependence, tolerance, withdraw. These unwanted effects can severely limit their use.
The known ion channel-blocking agents and opioids have been very effective in pain management. However, they have restricted use because of several potentially severe side effects. Therefore, there is a current need for pharmaceutical agents that retain the analgesic properties of the known ion channel-blocking agents and opioids, but that have reduced side effect profiles. A single agent that has both ion channel-blocking ability and opioid binding ability may be particularly useful in pain management because of an additive or synergistic analgesic effect from a duel biochemical mechanism of action. This additive or synergistic analgesic effect would result in lower drug concentrations required for pain relief and therefore reduced side effect profiles.